Objective To determine the protective effect and of glycyrrhetinic acid(GA)on sunitinib-induced liver injury related mechanism.Methods Firstly,adverse event(AE)data of sunitinib and other drugs used for the treatment of metastatic renal cell carcinoma and gastrointestinal stromal tumors were collected from the US Food and Drug Administration Adverse Event Reporting System(FAERS)database.The signal association strength between the drugs and AEs was calculated with Bayesian method,and the hepatotoxicity risk of sunitinib was compared with that of other antitumor drugs.At the animal level,mice were randomly divided into a normal control group,a sunitinib group(120 mg·kg-1),a sunitinib plus low-dose GA group(10 mg·kg-1),and a sunitinib plus high-dose GA group(20 mg·kg-1),with 5 mice in each group.The mice in each group were orally administered daily for 2 weeks.After the treatment,the levels of serum alanine aminotransferase(ALT)and aspartate aminotransferase(AST)were measured.Hematoxylin-eosin(HE)staining was used to observe the pathological changes in the liver tissues.The levels of lipid peroxides(LPO),malondialdehyde(MDA),and iron(Fe)in the liver tissues were determined by assay kits.Western blot was used to detect the protein expression of nuclear factor E2-related factor 2(Nrf2),solute carrier family 7 member 11(SLC7A11),heme oxygenase-1(HO-1),and glutathione peroxidase 4(GPX4).Results The signal mining of the FAERS database showed that sunitinib had a more significant association with the liver AEs than did other drugs in the treatment of metastatic renal cell carcinoma and gastrointestinal stromal tumors,especially for patients with jaundice,high bilirubin levels,AST elevation,and liver failure.In the animal experiment,compared with the normal control group,the serum ALT and AST levels in the sunitinib group significantly increased.HE staining showed obvious disorder in the liver cell cords,vacuolar degeneration,and inflammatory cell infiltration.The levels of LPO,MDA,and Fe were significantly increased,and the protein expression of Nrf2,SLC7A11,HO-1,and GPX4 were decreased.After combining GA,the levels of ALT and AST were significantly decreased,the pathological damage in the liver tissue was partially restored,the levels of LPO,MDA,and Fe were decreased,and the protein expression of Nrf2,SLC7A11,HO-1,and GPX4 were increased.Conclusion GA can effectively alleviate sunitinib-induced liver injury,whose mechanism may be related to the inhibition of ferroptosis.
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